The incidence of mammary cancer is known to increase with increasing age. It is well established that mammary tumorigenesis is strongly influenced by reproductive hormones, and specific hormone receptor assays have been employed to predict the responsiveness of mammary cancer cells to particular hormones. However, little is known about the quantitative changes in reproductive hormonal levels during aging, and even less is known about the possible effects of such changes in hormonal milieu on the susceptibility of mammary cells to carcinogenesis. Our proposed research program is designed first to quantitate the hormonal changes associated with aging and to elucidate the role of these changes, as well as hormone-receptor interaction, on the incidence and growth of spontaneous mammary tumors in the female rat. Circulating levels of reproductive hormones and tissue content of hormone receptors will be quantitatively measured at various phases of aging. The effect of endocrine ablation and of hormone replacement therapy on growth of spontaneous mammary tumors will be studied. In the second phase of this research, we will test the age-related changes in hormonal milieu on the susceptibility of mammary cells to carcinogenesis. Development of spontaneous mammary tumors will be examined in aged rats devoid of certain reproductive hormones as well as in young rats exposed to levels of reproductive hormones found in aging rats. Finally, the age-related changes in susceptibility to a chemical carcinogen (7, 12-dimethylbenz(alpha)anthracene) will be determined. Our proposed research program involves the use of a colony of 100 Long-Evans female rats already established in our laboratory. These animals are presently almost two years old and 20% of them have developed spontaneous mammary tumors.